#
# Copyright (C) 2018-2025 Susan H. Leung and other RDKit contributors
#         All Rights Reserved
#
import math
import os
import sys
import unittest
from datetime import datetime, timedelta

from rdkit import Chem, DataStructs, RDConfig
from rdkit.Chem.MolStandardize import rdMolStandardize
from rdkit.Chem import rdCIPLabeler
from rdkit.Chem.rdchem import Atom
from rdkit.Geometry import rdGeometry as geom


class TestCase(unittest.TestCase):

  def setUp(self):
    pass

  def test1Cleanup(self):
    mol = Chem.MolFromSmiles("CCC(=O)O[Na]")
    nmol = rdMolStandardize.Cleanup(mol)
    self.assertEqual(Chem.MolToSmiles(nmol), "CCC(=O)[O-].[Na+]")

  def test2StandardizeSmiles(self):
    self.assertEqual(rdMolStandardize.StandardizeSmiles("CCC(=O)O[Na]"), "CCC(=O)[O-].[Na+]")

  def test3Parents(self):
    mol = Chem.MolFromSmiles("[Na]OC(=O)c1ccccc1")
    nmol = rdMolStandardize.FragmentParent(mol)
    self.assertEqual(Chem.MolToSmiles(nmol), "O=C([O-])c1ccccc1")

    mol = Chem.MolFromSmiles("C[NH+](C)(C).[Cl-]")
    nmol = rdMolStandardize.ChargeParent(mol)
    self.assertEqual(Chem.MolToSmiles(nmol), "CN(C)C")

    mol = Chem.MolFromSmiles("[O-]CCCC=CO.[Na+]")
    nmol = rdMolStandardize.TautomerParent(mol)
    self.assertEqual(Chem.MolToSmiles(nmol), "O=CCCCC[O-].[Na+]")
    nmol = rdMolStandardize.TautomerParent(mol, skipStandardize=True)
    # same answer because of the standardization at the end
    self.assertEqual(Chem.MolToSmiles(nmol), "O=CCCCC[O-].[Na+]")

    mol = Chem.MolFromSmiles("C[C@](F)(Cl)C/C=C/[C@H](F)Cl")
    nmol = rdMolStandardize.StereoParent(mol)
    self.assertEqual(Chem.MolToSmiles(nmol), "CC(F)(Cl)CC=CC(F)Cl")

    mol = Chem.MolFromSmiles("[12CH3][13CH3]")
    nmol = rdMolStandardize.IsotopeParent(mol)
    self.assertEqual(Chem.MolToSmiles(nmol), "CC")

    mol = Chem.MolFromSmiles("[Na]Oc1c([12C@H](F)Cl)c(O[2H])c(C(=O)O)cc1CC=CO")
    nmol = rdMolStandardize.SuperParent(mol)
    self.assertEqual(Chem.MolToSmiles(nmol), "O=CCCc1cc(C(=O)O)c(O)c(C(F)Cl)c1O")
    mol = Chem.MolFromSmiles("[Na]Oc1c([12C@H](F)Cl)c(O[2H])c(C(=O)O)cc1CC=CO")
    nmol = rdMolStandardize.SuperParent(mol, skipStandardize=True)
    self.assertEqual(Chem.MolToSmiles(nmol), "O=CCCc1cc(C(=O)[O-])c(O)c(C(F)Cl)c1O.[Na+]")

  def test4Normalize(self):
    mol = Chem.MolFromSmiles(r"C[N+](C)=C\C=C\[O-]")
    nmol = rdMolStandardize.Normalize(mol)
    self.assertEqual(Chem.MolToSmiles(nmol), "CN(C)C=CC=O")

  def test4Reionize(self):
    mol = Chem.MolFromSmiles("C1=C(C=CC(=C1)[S]([O-])=O)[S](O)(=O)=O")
    nmol = rdMolStandardize.Reionize(mol)
    self.assertEqual(Chem.MolToSmiles(nmol), "O=S(O)c1ccc(S(=O)(=O)[O-])cc1")

  def test5Metal(self):
    mol = Chem.MolFromSmiles("C1(CCCCC1)[Zn]Br")
    md = rdMolStandardize.MetalDisconnector()
    nm = md.Disconnect(mol)
    self.assertEqual(Chem.MolToSmiles(nm), "[Br-].[CH-]1CCCCC1.[Zn+2]")
    nm = Chem.Mol(mol)
    md.DisconnectInPlace(nm)
    self.assertEqual(Chem.MolToSmiles(nm), "[Br-].[CH-]1CCCCC1.[Zn+2]")

    # test user defined metal_nof
    md.SetMetalNof(
      Chem.MolFromSmarts(
        "[Li,K,Rb,Cs,Fr,Be,Mg,Ca,Sr,Ba,Ra,Sc,Ti,V,Cr,Mn,Fe,Co,Ni,Cu,Zn,Al,Ga,Y,Zr,Nb,Mo,Tc,Ru,Rh,Pd,Ag,Cd,In,Sn,Hf,Ta,W,Re,Os,Ir,Pt,Au,Hg,Tl,Pb,Bi]~[N,O,F]"
      ))
    mol2 = Chem.MolFromSmiles("CCC(=O)[O][Na]")
    nm2 = md.Disconnect(mol2)
    self.assertEqual(Chem.MolToSmiles(nm2), "CCC(=O)[O][Na]")

    # Split with organometallics disconnector, two ways.
    rufile = os.path.join(RDConfig.RDBaseDir, 'Code', 'GraphMol', 'MolStandardize', 'test_data',
                          'ruthenium.mol')
    rumol = Chem.MolFromMolFile(rufile)
    disrumol = rdMolStandardize.DisconnectOrganometallics(rumol)
    self.assertEqual(Chem.MolToSmiles(disrumol),
                     "[Cl-].[Cl-].[Cl-].[Cl-].[Ru+2].[Ru+2].c1ccccc1.c1ccccc1")

    opts = rdMolStandardize.MetalDisconnectorOptions()
    opts.splitGrignards = True
    opts.splitAromaticC = True
    opts.adjustCharges = False
    opts.removeHapticDummies = True
    def_opts = rdMolStandardize.MetalDisconnectorOptions()
    self.assertNotEqual(def_opts.splitGrignards, opts.splitGrignards)
    self.assertNotEqual(def_opts.splitAromaticC, opts.splitAromaticC)
    self.assertNotEqual(def_opts.adjustCharges, opts.adjustCharges)
    self.assertNotEqual(def_opts.removeHapticDummies, opts.removeHapticDummies)

    md = rdMolStandardize.MetalDisconnector(opts)

    grigfile = os.path.join(RDConfig.RDBaseDir, 'Code', 'GraphMol', 'MolStandardize', 'test_data',
                            'grignard_2.mol')
    grigmol = Chem.MolFromMolFile(grigfile)
    disgrigmol = md.Disconnect(grigmol)
    self.assertEqual(Chem.MolToSmiles(disgrigmol), "[Cl-].[Mg+2].[c-]1ccccc1")

    # and passing in the options explicitly
    disrumol = rdMolStandardize.DisconnectOrganometallics(rumol, opts)
    self.assertEqual(Chem.MolToSmiles(disrumol),
                     "[Cl-].[Cl-].[Cl-].[Cl-].[Ru+2].[Ru+2].c1ccccc1.c1ccccc1")

  def test6Charge(self):
    mol = Chem.MolFromSmiles("C1=C(C=CC(=C1)[S]([O-])=O)[S](O)(=O)=O")
    # instantiate with default acid base pair library
    reionizer = rdMolStandardize.Reionizer()
    nm = reionizer.reionize(mol)
    self.assertEqual(Chem.MolToSmiles(nm), "O=S(O)c1ccc(S(=O)(=O)[O-])cc1")

    nm = Chem.Mol(mol)
    reionizer.reionizeInPlace(nm)
    self.assertEqual(Chem.MolToSmiles(nm), "O=S(O)c1ccc(S(=O)(=O)[O-])cc1")

    # try reionize with another acid base pair library without the right
    # pairs
    abfile = os.path.join(RDConfig.RDBaseDir, 'Code', 'GraphMol', 'MolStandardize', 'test_data',
                          'acid_base_pairs2.txt')
    reionizer2 = rdMolStandardize.Reionizer(abfile)
    nm2 = reionizer2.reionize(mol)
    self.assertEqual(Chem.MolToSmiles(nm2), "O=S([O-])c1ccc(S(=O)(=O)O)cc1")

    # test Uncharger
    uncharger = rdMolStandardize.Uncharger()
    mol3 = Chem.MolFromSmiles("O=C([O-])c1ccccc1")
    nm3 = uncharger.uncharge(mol3)
    self.assertEqual(Chem.MolToSmiles(nm3), "O=C(O)c1ccccc1")
    nm3 = Chem.Mol(mol3)
    uncharger.unchargeInPlace(nm3)
    self.assertEqual(Chem.MolToSmiles(nm3), "O=C(O)c1ccccc1")

    # test canonical Uncharger
    uncharger = rdMolStandardize.Uncharger(canonicalOrder=False)
    mol3 = Chem.MolFromSmiles("C[N+](C)(C)CC(C(=O)[O-])CC(=O)[O-]")
    nm3 = uncharger.uncharge(mol3)
    self.assertEqual(Chem.MolToSmiles(nm3), "C[N+](C)(C)CC(CC(=O)[O-])C(=O)O")
    nm3 = Chem.Mol(mol3)
    uncharger.unchargeInPlace(nm3)
    self.assertEqual(Chem.MolToSmiles(nm3), "C[N+](C)(C)CC(CC(=O)[O-])C(=O)O")

    uncharger = rdMolStandardize.Uncharger(canonicalOrder=True)
    nm3 = uncharger.uncharge(mol3)
    self.assertEqual(Chem.MolToSmiles(nm3), "C[N+](C)(C)CC(CC(=O)O)C(=O)[O-]")
    nm3 = Chem.Mol(mol3)
    uncharger.unchargeInPlace(nm3)
    self.assertEqual(Chem.MolToSmiles(nm3), "C[N+](C)(C)CC(CC(=O)O)C(=O)[O-]")

  def test7Fragment(self):
    fragremover = rdMolStandardize.FragmentRemover()
    mol = Chem.MolFromSmiles("CN(C)C.Cl.Cl.Br")
    nm = fragremover.remove(mol)
    self.assertEqual(Chem.MolToSmiles(nm), "CN(C)C")

    nm = Chem.Mol(mol)
    fragremover.removeInPlace(nm)
    self.assertEqual(Chem.MolToSmiles(nm), "CN(C)C")

    lfragchooser = rdMolStandardize.LargestFragmentChooser()
    mol2 = Chem.MolFromSmiles("[N+](=O)([O-])[O-].[CH3+]")
    nm2 = lfragchooser.choose(mol2)
    self.assertEqual(Chem.MolToSmiles(nm2), "O=[N+]([O-])[O-]")
    nm2 = Chem.Mol(mol2)
    lfragchooser.chooseInPlace(nm2)
    self.assertEqual(Chem.MolToSmiles(nm2), "O=[N+]([O-])[O-]")

    lfragchooser2 = rdMolStandardize.LargestFragmentChooser(preferOrganic=True)
    nm3 = lfragchooser2.choose(mol2)
    self.assertEqual(Chem.MolToSmiles(nm3), "[CH3+]")
    nm3 = Chem.Mol(mol2)
    lfragchooser2.chooseInPlace(nm3)
    self.assertEqual(Chem.MolToSmiles(nm3), "[CH3+]")

    fragremover = rdMolStandardize.FragmentRemover(skip_if_all_match=True)
    mol = Chem.MolFromSmiles("[Na+].Cl.Cl.Br")
    nm = fragremover.remove(mol)
    self.assertEqual(nm.GetNumAtoms(), mol.GetNumAtoms())
    nm = Chem.Mol(mol)
    fragremover.removeInPlace(mol)
    self.assertEqual(nm.GetNumAtoms(), mol.GetNumAtoms())

    smi3 = "CNC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.c1cc2c(cc1C(=O)O)oc(n2)c3cc(cc(c3)Cl)Cl"

    lfParams = rdMolStandardize.CleanupParameters()
    lfrag_params = rdMolStandardize.LargestFragmentChooser(lfParams)
    mol3 = Chem.MolFromSmiles(smi3)
    lfrag3 = lfrag_params.choose(mol3)
    self.assertEqual(Chem.MolToSmiles(lfrag3), "CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO")

    lfParams = rdMolStandardize.CleanupParameters()
    lfParams.largestFragmentChooserCountHeavyAtomsOnly = True
    lfrag_params = rdMolStandardize.LargestFragmentChooser(lfParams)
    mol3 = Chem.MolFromSmiles(smi3)
    lfrag3 = lfrag_params.choose(mol3)
    self.assertEqual(Chem.MolToSmiles(lfrag3), "O=C(O)c1ccc2nc(-c3cc(Cl)cc(Cl)c3)oc2c1")

    lfParams = rdMolStandardize.CleanupParameters()
    lfParams.largestFragmentChooserUseAtomCount = False
    lfrag_params = rdMolStandardize.LargestFragmentChooser(lfParams)
    mol3 = Chem.MolFromSmiles(smi3)
    lfrag3 = lfrag_params.choose(mol3)
    self.assertEqual(Chem.MolToSmiles(lfrag3), "O=C(O)c1ccc2nc(-c3cc(Cl)cc(Cl)c3)oc2c1")

    smi4 = "CC.O=[Pb]=O"

    lfParams = rdMolStandardize.CleanupParameters()
    lfrag_params = rdMolStandardize.LargestFragmentChooser(lfParams)
    mol4 = Chem.MolFromSmiles(smi4)
    lfrag4 = lfrag_params.choose(mol4)
    self.assertEqual(Chem.MolToSmiles(lfrag4), "CC")

    lfParams = rdMolStandardize.CleanupParameters()
    lfParams.largestFragmentChooserCountHeavyAtomsOnly = True
    lfrag_params = rdMolStandardize.LargestFragmentChooser(lfParams)
    mol4 = Chem.MolFromSmiles(smi4)
    lfrag4 = lfrag_params.choose(mol4)
    self.assertEqual(Chem.MolToSmiles(lfrag4), "[O]=[Pb]=[O]")

    lfParams = rdMolStandardize.CleanupParameters()
    lfParams.largestFragmentChooserUseAtomCount = False
    lfrag_params = rdMolStandardize.LargestFragmentChooser(lfParams)
    mol4 = Chem.MolFromSmiles(smi4)
    lfrag4 = lfrag_params.choose(mol4)
    self.assertEqual(Chem.MolToSmiles(lfrag4), "[O]=[Pb]=[O]")

    lfParams = rdMolStandardize.CleanupParameters()
    lfParams.largestFragmentChooserCountHeavyAtomsOnly = True
    lfParams.preferOrganic = True
    lfrag_params = rdMolStandardize.LargestFragmentChooser(lfParams)
    mol4 = Chem.MolFromSmiles(smi4)
    lfrag4 = lfrag_params.choose(mol4)
    self.assertEqual(Chem.MolToSmiles(lfrag4), "CC")

    lfParams = rdMolStandardize.CleanupParameters()
    lfParams.largestFragmentChooserUseAtomCount = False
    lfParams.preferOrganic = True
    lfrag_params = rdMolStandardize.LargestFragmentChooser(lfParams)
    mol4 = Chem.MolFromSmiles(smi4)
    lfrag4 = lfrag_params.choose(mol4)
    self.assertEqual(Chem.MolToSmiles(lfrag4), "CC")

  def test8Normalize(self):
    normalizer = rdMolStandardize.Normalizer()
    mol = Chem.MolFromSmiles("C[n+]1ccccc1[O-]")
    nm = normalizer.normalize(mol)
    self.assertEqual(Chem.MolToSmiles(nm), "Cn1ccccc1=O")
    nm = Chem.Mol(mol)
    normalizer.normalizeInPlace(nm)
    self.assertEqual(Chem.MolToSmiles(nm), "Cn1ccccc1=O")

  def test9Validate(self):
    vm = rdMolStandardize.RDKitValidation()
    mol = Chem.MolFromSmiles("CO(C)C", sanitize=False)
    msg = vm.validate(mol)
    self.assertEqual(len(msg), 1)
    self.assertEqual(
      """INFO: [ValenceValidation] Explicit valence for atom # 1 O, 3, is greater than permitted""",
      msg[0])
    mol = Chem.MolFromSmiles("")
    msg = vm.validate(mol)
    self.assertEqual(len(msg), 1)
    self.assertEqual("ERROR: [NoAtomValidation] Molecule has no atoms", msg[0])
    vm.allowEmptyMolecules = True
    msg = vm.validate(mol)
    self.assertEqual(len(msg), 0)


    vm2 = rdMolStandardize.MolVSValidation([rdMolStandardize.FragmentValidation()])
    # with no argument it also works
    #    vm2 = rdMolStandardize.MolVSValidation()
    mol2 = Chem.MolFromSmiles("COc1cccc(C=N[N-]C(N)=O)c1[O-].O.O.O.O=[U+2]=O")
    msg2 = vm2.validate(mol2)
    self.assertEqual(len(msg2), 1)
    self.assertEqual("""INFO: [FragmentValidation] water/hydroxide is present""", msg2[0])

    vm3 = rdMolStandardize.MolVSValidation()
    mol3 = Chem.MolFromSmiles("C1COCCO1.O=C(NO)NO")
    msg3 = vm3.validate(mol3)
    self.assertEqual(len(msg3), 2)
    self.assertEqual("""INFO: [FragmentValidation] 1,2-dimethoxyethane is present""", msg3[0])
    self.assertEqual("""INFO: [FragmentValidation] 1,4-dioxane is present""", msg3[1])

    atomic_no = [6, 7, 8]
    allowed_atoms = [Atom(i) for i in atomic_no]
    vm4 = rdMolStandardize.AllowedAtomsValidation(allowed_atoms)
    mol4 = Chem.MolFromSmiles("CC(=O)CF")
    msg4 = vm4.validate(mol4)
    self.assertEqual(len(msg4), 1)
    self.assertEqual("""INFO: [AllowedAtomsValidation] Atom F is not in allowedAtoms list""",
                     msg4[0])

    atomic_no = [9, 17, 35]
    disallowed_atoms = [Atom(i) for i in atomic_no]
    vm5 = rdMolStandardize.DisallowedAtomsValidation(disallowed_atoms)
    mol5 = Chem.MolFromSmiles("CC(=O)CF")
    msg5 = vm5.validate(mol5)
    self.assertEqual(len(msg5), 1)
    self.assertEqual("""INFO: [DisallowedAtomsValidation] Atom F is in disallowedAtoms list""",
                     msg5[0])

    mol6 = Chem.MolFromSmiles("[3CH4]")
    vm6a = rdMolStandardize.IsotopeValidation()
    msg6a = vm6a.validate(mol6)
    self.assertEqual(len(msg6a), 1)
    self.assertEqual("INFO: [IsotopeValidation] Molecule contains isotope 3C", msg6a[0])
    vm6b = rdMolStandardize.IsotopeValidation(True)
    msg6b = vm6b.validate(mol6)
    self.assertEqual(len(msg6b), 1)
    self.assertEqual("ERROR: [IsotopeValidation] The molecule contains an unknown isotope: 3C",
                     msg6b[0])

    msg999 = rdMolStandardize.ValidateSmiles("ClCCCl.c1ccccc1O")
    self.assertEqual(len(msg999), 1)
    self.assertEqual("""INFO: [FragmentValidation] 1,2-dichloroethane is present""", msg999[0])

  def test10NormalizeFromData(self):
    data = """//	Name	SMIRKS
Nitro to N+(O-)=O	[N,P,As,Sb;X3:1](=[O,S,Se,Te:2])=[O,S,Se,Te:3]>>[*+1:1]([*-1:2])=[*:3]
Sulfone to S(=O)(=O)	[S+2:1]([O-:2])([O-:3])>>[S+0:1](=[O-0:2])(=[O-0:3])
Pyridine oxide to n+O-	[n:1]=[O:2]>>[n+:1][O-:2]
// Azide to N=N+=N-	[*,H:1][N:2]=[N:3]#[N:4]>>[*,H:1][N:2]=[N+:3]=[N-:4]
"""
    normalizer1 = rdMolStandardize.Normalizer()
    params = rdMolStandardize.CleanupParameters()
    normalizer2 = rdMolStandardize.NormalizerFromData(data, params)

    imol = Chem.MolFromSmiles("O=N(=O)CCN=N#N", sanitize=False)
    mol1 = normalizer1.normalize(imol)
    mol2 = normalizer2.normalize(imol)
    self.assertEqual(Chem.MolToSmiles(imol), "N#N=NCCN(=O)=O")
    self.assertEqual(Chem.MolToSmiles(mol1), "[N-]=[N+]=NCC[N+](=O)[O-]")
    self.assertEqual(Chem.MolToSmiles(mol2), "N#N=NCC[N+](=O)[O-]")

  def test11FragmentParams(self):
    data = """//   Name	SMARTS
fluorine	[F]
chlorine	[Cl]
        """
    fragremover = rdMolStandardize.FragmentRemoverFromData(data)
    mol = Chem.MolFromSmiles("CN(C)C.Cl.Cl.Br")
    nm = fragremover.remove(mol)
    self.assertEqual(Chem.MolToSmiles(nm), "Br.CN(C)C")

  def test12ChargeParams(self):
    params = """// The default list of AcidBasePairs, sorted from strongest to weakest.
// This list is derived from the Food and Drug: Administration Substance
// Registration System Standard Operating Procedure guide.
//
//	Name	Acid	Base
-SO2H	[!O][SD3](=O)[OH]	[!O][SD3](=O)[O-]
-SO3H	[!O]S(=O)(=O)[OH]	[!O]S(=O)(=O)[O-]
"""
    mol = Chem.MolFromSmiles("C1=C(C=CC(=C1)[S]([O-])=O)[S](O)(=O)=O")
    # instantiate with default acid base pair library
    reionizer = rdMolStandardize.ReionizerFromData(params, [])
    print("done")
    nm = reionizer.reionize(mol)
    self.assertEqual(Chem.MolToSmiles(nm), "O=S([O-])c1ccc(S(=O)(=O)O)cc1")

  def test13Tautomers(self):
    enumerator = rdMolStandardize.TautomerEnumerator()
    m = Chem.MolFromSmiles("C1(=CCCCC1)O")
    ctaut = enumerator.Canonicalize(m)
    self.assertEqual(Chem.MolToSmiles(ctaut), "O=C1CCCCC1")

    params = rdMolStandardize.CleanupParameters()
    enumerator = rdMolStandardize.TautomerEnumerator(params)
    m = Chem.MolFromSmiles("C1(=CCCCC1)O")
    ctaut = enumerator.Canonicalize(m)
    self.assertEqual(Chem.MolToSmiles(ctaut), "O=C1CCCCC1")

    taut_res = enumerator.Enumerate(m)
    self.assertEqual(len(taut_res), 2)
    ctauts = list(sorted(Chem.MolToSmiles(x) for x in taut_res))
    self.assertEqual(ctauts, ['O=C1CCCCC1', 'OC1=CCCCC1'])
    self.assertEqual(list(taut_res.smiles), ['O=C1CCCCC1', 'OC1=CCCCC1'])
    # this tests the non-templated overload
    self.assertEqual(Chem.MolToSmiles(enumerator.PickCanonical(taut_res)), "O=C1CCCCC1")
    # this tests the templated overload
    self.assertEqual(Chem.MolToSmiles(enumerator.PickCanonical(set(taut_res()))), "O=C1CCCCC1")
    with self.assertRaises(TypeError):
      enumerator.PickCanonical(1)
    with self.assertRaises(TypeError):
      enumerator.PickCanonical([0, 1])
    self.assertEqual(
      Chem.MolToSmiles(
        enumerator.PickCanonical(Chem.MolFromSmiles(x) for x in ['O=C1CCCCC1', 'OC1=CCCCC1'])),
      "O=C1CCCCC1")

    def scorefunc1(mol):
      ' stupid tautomer scoring function '
      p = Chem.MolFromSmarts('[OH]')
      return len(mol.GetSubstructMatches(p))

    def scorefunc2(mol):
      ' stupid tautomer scoring function '
      p = Chem.MolFromSmarts('O=C')
      return len(mol.GetSubstructMatches(p))

    m = Chem.MolFromSmiles("C1(=CCCCC1)O")
    ctaut = enumerator.Canonicalize(m, scorefunc1)
    self.assertEqual(Chem.MolToSmiles(ctaut), "OC1=CCCCC1")
    ctaut = enumerator.Canonicalize(m, scorefunc2)
    self.assertEqual(Chem.MolToSmiles(ctaut), "O=C1CCCCC1")
    # make sure lambdas work
    ctaut = enumerator.Canonicalize(m,
                                    lambda x: len(x.GetSubstructMatches(Chem.MolFromSmarts('C=O'))))
    self.assertEqual(Chem.MolToSmiles(ctaut), "O=C1CCCCC1")

    # make sure we behave if we return something bogus from the scoring function
    with self.assertRaises(TypeError):
      ctaut = enumerator.Canonicalize(m, lambda x: 'fail')

    self.assertEqual(enumerator.ScoreTautomer(Chem.MolFromSmiles('N=c1[nH]cccc1')), 99)
    self.assertEqual(enumerator.ScoreTautomer(Chem.MolFromSmiles('Nc1ncccc1')), 100)

    def scorefunc2(mol):
      ' stupid tautomer scoring function '
      p = Chem.MolFromSmarts('O=C')
      return len(mol.GetSubstructMatches(p))

    m = Chem.MolFromSmiles("C1(=CCCCC1)O")
    ctaut = enumerator.Canonicalize(m, scorefunc1)
    self.assertEqual(Chem.MolToSmiles(ctaut), "OC1=CCCCC1")
    ctaut = enumerator.Canonicalize(m, scorefunc2)
    self.assertEqual(Chem.MolToSmiles(ctaut), "O=C1CCCCC1")
    # make sure lambdas work
    ctaut = enumerator.Canonicalize(m,
                                    lambda x: len(x.GetSubstructMatches(Chem.MolFromSmarts('C=O'))))
    self.assertEqual(Chem.MolToSmiles(ctaut), "O=C1CCCCC1")

    # make sure we behave if we return something bogus from the scoring function
    with self.assertRaises(TypeError):
      ctaut = enumerator.Canonicalize(m, lambda x: 'fail')

    self.assertEqual(enumerator.ScoreTautomer(Chem.MolFromSmiles('N=c1[nH]cccc1')), 99)
    self.assertEqual(enumerator.ScoreTautomer(Chem.MolFromSmiles('Nc1ncccc1')), 100)

    res = enumerator.Enumerate(m)
    # this test the specialized overload
    ctaut = enumerator.PickCanonical(res, scorefunc1)
    self.assertEqual(Chem.MolToSmiles(ctaut), "OC1=CCCCC1")
    ctaut = enumerator.PickCanonical(res, scorefunc2)
    self.assertEqual(Chem.MolToSmiles(ctaut), "O=C1CCCCC1")
    # make sure lambdas work
    ctaut = enumerator.PickCanonical(
      res, lambda x: len(x.GetSubstructMatches(Chem.MolFromSmarts('C=O'))))
    self.assertEqual(Chem.MolToSmiles(ctaut), "O=C1CCCCC1")
    # make sure we behave if we return something bogus from the scoring function
    with self.assertRaises(TypeError):
      ctaut = enumerator.PickCanonical(res, lambda x: 'fail')
    # this test the non-specialized overload
    ctaut = enumerator.PickCanonical(set(res()), scorefunc1)
    self.assertEqual(Chem.MolToSmiles(ctaut), "OC1=CCCCC1")
    ctaut = enumerator.PickCanonical(set(res()), scorefunc2)
    self.assertEqual(Chem.MolToSmiles(ctaut), "O=C1CCCCC1")
    # make sure lambdas work
    ctaut = enumerator.PickCanonical(
      set(res()), lambda x: len(x.GetSubstructMatches(Chem.MolFromSmarts('C=O'))))
    self.assertEqual(Chem.MolToSmiles(ctaut), "O=C1CCCCC1")
    # make sure we behave if we return something bogus from the scoring function
    with self.assertRaises(TypeError):
      ctaut = enumerator.PickCanonical(set(res()), lambda x: 'fail')

  def test14TautomerDetails(self):
    enumerator = rdMolStandardize.TautomerEnumerator()
    m = Chem.MolFromSmiles("c1ccccc1CN=c1[nH]cccc1")
    taut_res = enumerator.Enumerate(m)
    self.assertEqual(len(taut_res.tautomers), 2)
    self.assertEqual(taut_res.modifiedAtoms, (7, 9))
    self.assertEqual(len(taut_res.modifiedBonds), 7)
    self.assertEqual(taut_res.modifiedBonds, (7, 8, 9, 10, 11, 12, 14))

    taut_res = enumerator.Enumerate(m)
    self.assertEqual(len(taut_res.tautomers), 2)
    self.assertEqual(taut_res.modifiedAtoms, (7, 9))

    taut_res = enumerator.Enumerate(m)
    self.assertEqual(len(taut_res.tautomers), 2)
    self.assertEqual(len(taut_res.modifiedBonds), 7)
    self.assertEqual(taut_res.modifiedBonds, (7, 8, 9, 10, 11, 12, 14))

  def test15EnumeratorParams(self):
    # Test a structure with hundreds of tautomers.
    smi68 = "[H][C](CO)(NC(=O)C1=C(O)C(O)=CC=C1)C(O)=O"
    m68 = Chem.MolFromSmiles(smi68)

    enumerator = rdMolStandardize.TautomerEnumerator()
    res68 = enumerator.Enumerate(m68)
    self.assertEqual(len(res68), 72)
    self.assertEqual(len(res68.tautomers), len(res68))
    self.assertEqual(res68.status, rdMolStandardize.TautomerEnumeratorStatus.Completed)

    enumerator = rdMolStandardize.GetV1TautomerEnumerator()
    res68 = enumerator.Enumerate(m68)
    self.assertEqual(len(res68), 292)
    self.assertEqual(len(res68.tautomers), len(res68))
    self.assertEqual(res68.status, rdMolStandardize.TautomerEnumeratorStatus.MaxTransformsReached)

    params = rdMolStandardize.CleanupParameters()
    params.maxTautomers = 50
    enumerator = rdMolStandardize.TautomerEnumerator(params)
    res68 = enumerator.Enumerate(m68)
    self.assertEqual(len(res68), 50)
    self.assertEqual(res68.status, rdMolStandardize.TautomerEnumeratorStatus.MaxTautomersReached)


    origVal = Chem.GetUseLegacyStereoPerception()
    for useLegacy in (True, False):
      Chem.SetUseLegacyStereoPerception(useLegacy)

      sAlaSmi = "C[C@H](N)C(=O)O"
      sAla = Chem.MolFromSmiles(sAlaSmi)
      rdCIPLabeler.AssignCIPLabels(sAla)
      # test remove (S)-Ala stereochemistry
      self.assertEqual(sAla.GetAtomWithIdx(1).GetChiralTag(), Chem.ChiralType.CHI_TETRAHEDRAL_CCW)
      self.assertEqual(sAla.GetAtomWithIdx(1).GetProp("_CIPCode"), "S")
      params = rdMolStandardize.CleanupParameters()
      params.tautomerRemoveSp3Stereo = True
      enumerator = rdMolStandardize.TautomerEnumerator(params)
      res = enumerator.Enumerate(sAla)
      for taut in res:
        self.assertEqual(taut.GetAtomWithIdx(1).GetChiralTag(), Chem.ChiralType.CHI_UNSPECIFIED)
        self.assertFalse(taut.GetAtomWithIdx(1).HasProp("_CIPCode"))
      for taut in res.tautomers:
        self.assertEqual(taut.GetAtomWithIdx(1).GetChiralTag(), Chem.ChiralType.CHI_UNSPECIFIED)
        self.assertFalse(taut.GetAtomWithIdx(1).HasProp("_CIPCode"))
      for i, taut in enumerate(res):
        self.assertEqual(Chem.MolToSmiles(taut), Chem.MolToSmiles(res.tautomers[i]))
      self.assertEqual(len(res), len(res.smiles))
      self.assertEqual(len(res), len(res.tautomers))
      self.assertEqual(len(res), len(res()))
      self.assertEqual(len(res), len(res.smilesTautomerMap))
      for i, taut in enumerate(res.tautomers):
        self.assertEqual(Chem.MolToSmiles(taut), Chem.MolToSmiles(res[i]))
        self.assertEqual(Chem.MolToSmiles(taut), res.smiles[i])
        self.assertEqual(Chem.MolToSmiles(taut),
                        Chem.MolToSmiles(res.smilesTautomerMap.values()[i].tautomer))
      for i, k in enumerate(res.smilesTautomerMap.keys()):
        self.assertEqual(k, res.smiles[i])
      for i, v in enumerate(res.smilesTautomerMap.values()):
        self.assertEqual(Chem.MolToSmiles(v.tautomer), Chem.MolToSmiles(res[i]))
      for i, (k, v) in enumerate(res.smilesTautomerMap.items()):
        self.assertEqual(k, res.smiles[i])
        self.assertEqual(Chem.MolToSmiles(v.tautomer), Chem.MolToSmiles(res[i]))
      for i, smiles in enumerate(res.smiles):
        self.assertEqual(smiles, Chem.MolToSmiles(res[i]))
        self.assertEqual(smiles, res.smilesTautomerMap.keys()[i])
      self.assertEqual(Chem.MolToSmiles(res.tautomers[-1]), Chem.MolToSmiles(res[-1]))
      self.assertEqual(Chem.MolToSmiles(res[-1]), Chem.MolToSmiles(res[len(res) - 1]))
      self.assertEqual(Chem.MolToSmiles(res.tautomers[-1]),
                      Chem.MolToSmiles(res.tautomers[len(res) - 1]))
      with self.assertRaises(IndexError):
        res[len(res)]
      with self.assertRaises(IndexError):
        res[-len(res) - 1]
      with self.assertRaises(IndexError):
        res.tautomers[len(res)]
      with self.assertRaises(IndexError):
        res.tautomers[-len(res.tautomers) - 1]

      # test retain (S)-Ala stereochemistry
      self.assertEqual(sAla.GetAtomWithIdx(1).GetChiralTag(), Chem.ChiralType.CHI_TETRAHEDRAL_CCW)
      self.assertEqual(sAla.GetAtomWithIdx(1).GetProp("_CIPCode"), "S")
      params = rdMolStandardize.CleanupParameters()
      params.tautomerRemoveSp3Stereo = False
      enumerator = rdMolStandardize.TautomerEnumerator(params)
      res = enumerator.Enumerate(sAla)
      for taut in res:
        rdCIPLabeler.AssignCIPLabels(taut)
        tautAtom = taut.GetAtomWithIdx(1)
        if (tautAtom.GetHybridization() == Chem.HybridizationType.SP3):
          self.assertEqual(tautAtom.GetChiralTag(), Chem.ChiralType.CHI_TETRAHEDRAL_CCW)
          self.assertTrue(tautAtom.HasProp("_CIPCode"))
          self.assertEqual(tautAtom.GetProp("_CIPCode"), "S")
        else:
          self.assertFalse(tautAtom.HasProp("_CIPCode"))
          self.assertEqual(tautAtom.GetChiralTag(), Chem.ChiralType.CHI_UNSPECIFIED)

      eEnolSmi = "C/C=C/O"
      eEnol = Chem.MolFromSmiles(eEnolSmi)
      if useLegacy:
        self.assertEqual(eEnol.GetBondWithIdx(1).GetStereo(), Chem.BondStereo.STEREOE)
      else:
        self.assertEqual(eEnol.GetBondWithIdx(1).GetStereo(), Chem.BondStereo.STEREOTRANS)
      # test remove enol E stereochemistry
      params = rdMolStandardize.CleanupParameters()
      params.tautomerRemoveBondStereo = True
      enumerator = rdMolStandardize.TautomerEnumerator(params)
      res = enumerator.Enumerate(eEnol)
      for taut in res.tautomers:
        self.assertEqual(taut.GetBondWithIdx(1).GetStereo(), Chem.BondStereo.STEREONONE)
      # test retain enol E stereochemistry
      params = rdMolStandardize.CleanupParameters()
      params.tautomerRemoveBondStereo = False
      enumerator = rdMolStandardize.TautomerEnumerator(params)
      res = enumerator.Enumerate(eEnol)
      for taut in res.tautomers:
        if (taut.GetBondWithIdx(1).GetBondType() == Chem.BondType.DOUBLE):
          if useLegacy:
            self.assertEqual(taut.GetBondWithIdx(1).GetStereo(), Chem.BondStereo.STEREOE)
          else:
            self.assertEqual(taut.GetBondWithIdx(1).GetStereo(), Chem.BondStereo.STEREOTRANS)

      zEnolSmi = "C/C=C\\O"
      zEnol = Chem.MolFromSmiles(zEnolSmi)
      if useLegacy:
        self.assertEqual(zEnol.GetBondWithIdx(1).GetStereo(), Chem.BondStereo.STEREOZ)
      else:
        self.assertEqual(zEnol.GetBondWithIdx(1).GetStereo(), Chem.BondStereo.STEREOCIS)
      # test remove enol Z stereochemistry
      params = rdMolStandardize.CleanupParameters()
      params.tautomerRemoveBondStereo = True
      enumerator = rdMolStandardize.TautomerEnumerator(params)
      res = enumerator.Enumerate(zEnol)
      for taut in res:
        self.assertEqual(taut.GetBondWithIdx(1).GetStereo(), Chem.BondStereo.STEREONONE)
      # test retain enol Z stereochemistry
      params = rdMolStandardize.CleanupParameters()
      params.tautomerRemoveBondStereo = False
      enumerator = rdMolStandardize.TautomerEnumerator(params)
      res = enumerator.Enumerate(zEnol)
      for taut in res:
        if (taut.GetBondWithIdx(1).GetBondType() == Chem.BondType.DOUBLE):
          if useLegacy:
            self.assertEqual(taut.GetBondWithIdx(1).GetStereo(), Chem.BondStereo.STEREOZ)
          else:
            self.assertEqual(taut.GetBondWithIdx(1).GetStereo(), Chem.BondStereo.STEREOCIS)
    Chem.SetUseLegacyStereoPerception(origVal)

    chembl2024142Smi = "[2H]C1=C(C(=C2C(=C1[2H])C(=O)C(=C(C2=O)C([2H])([2H])[2H])C/C=C(\\C)/CC([2H])([2H])/C=C(/CC/C=C(\\C)/CCC=C(C)C)\\C([2H])([2H])[2H])[2H])[2H]"
    chembl2024142 = Chem.MolFromSmiles(chembl2024142Smi)
    params = Chem.RemoveHsParameters()
    params.removeAndTrackIsotopes = True
    chembl2024142 = Chem.RemoveHs(chembl2024142, params)
    self.assertTrue(chembl2024142.GetAtomWithIdx(12).HasProp("_isotopicHs"))
    # test remove isotopic Hs involved in tautomerism
    params = rdMolStandardize.CleanupParameters()
    params.tautomerRemoveIsotopicHs = True
    enumerator = rdMolStandardize.TautomerEnumerator(params)
    res = enumerator.Enumerate(chembl2024142)
    for taut in res:
      self.assertFalse(taut.GetAtomWithIdx(12).HasProp("_isotopicHs"))
    # test retain isotopic Hs involved in tautomerism
    params = rdMolStandardize.CleanupParameters()
    params.tautomerRemoveIsotopicHs = False
    enumerator = rdMolStandardize.TautomerEnumerator(params)
    res = enumerator.Enumerate(chembl2024142)
    for taut in res:
      self.assertTrue(taut.GetAtomWithIdx(12).HasProp("_isotopicHs"))

  def test16EnumeratorCallback(self):

    class MyTautomerEnumeratorCallback(rdMolStandardize.TautomerEnumeratorCallback):

      def __init__(self, parent, timeout_ms):
        super().__init__()
        self._parent = parent
        self._timeout = timedelta(milliseconds=timeout_ms)
        self._start_time = datetime.now()

      def __call__(self, mol, res):
        self._parent.assertTrue(isinstance(mol, Chem.Mol))
        self._parent.assertTrue(isinstance(res, rdMolStandardize.TautomerEnumeratorResult))
        return (datetime.now() - self._start_time < self._timeout)

    class MyBrokenCallback(rdMolStandardize.TautomerEnumeratorCallback):
      pass

    class MyBrokenCallback2(rdMolStandardize.TautomerEnumeratorCallback):
      __call__ = 1

    # Test a structure with hundreds of tautomers.
    smi68 = "[H][C](CO)(NC(=O)C1=C(O)C(O)=CC=C1)C(O)=O"
    m68 = Chem.MolFromSmiles(smi68)

    def createV1Enumerator():
      enumerator = rdMolStandardize.GetV1TautomerEnumerator()
      enumerator.SetMaxTransforms(10000)
      enumerator.SetMaxTautomers(10000)
      return enumerator

    params = rdMolStandardize.CleanupParameters()
    params.maxTransforms = 10000
    params.maxTautomers = 10000

    enumerator = createV1Enumerator()
    enumerator.SetCallback(MyTautomerEnumeratorCallback(self, 50.0))
    res68 = enumerator.Enumerate(m68)
    # either the enumeration was canceled due to timeout
    # or it has completed very quickly
    hasReachedTimeout = (len(res68.tautomers) < 375
                         and res68.status == rdMolStandardize.TautomerEnumeratorStatus.Canceled)
    hasCompleted = (len(res68.tautomers) == 375
                    and res68.status == rdMolStandardize.TautomerEnumeratorStatus.Completed)
    if hasReachedTimeout:
      print("Enumeration was canceled due to timeout (50 ms)", file=sys.stderr)
    if hasCompleted:
      print("Enumeration has completed", file=sys.stderr)
    self.assertTrue(hasReachedTimeout or hasCompleted)
    self.assertTrue(hasReachedTimeout ^ hasCompleted)

    enumerator = createV1Enumerator()
    enumerator.SetCallback(MyTautomerEnumeratorCallback(self, 10000.0))
    res68 = enumerator.Enumerate(m68)
    # either the enumeration completed
    # or it ran very slowly and was canceled due to timeout
    hasReachedTimeout = (len(res68.tautomers) < 375
                         and res68.status == rdMolStandardize.TautomerEnumeratorStatus.Canceled)
    hasCompleted = (len(res68.tautomers) == 375
                    and res68.status == rdMolStandardize.TautomerEnumeratorStatus.Completed)
    if hasReachedTimeout:
      print("Enumeration was canceled due to timeout (10 s)", file=sys.stderr)
    if hasCompleted:
      print("Enumeration has completed", file=sys.stderr)
    self.assertTrue(hasReachedTimeout or hasCompleted)
    self.assertTrue(hasReachedTimeout ^ hasCompleted)

    enumerator = rdMolStandardize.TautomerEnumerator(params)
    with self.assertRaises(AttributeError):
      enumerator.SetCallback(MyBrokenCallback())
    with self.assertRaises(AttributeError):
      enumerator.SetCallback(MyBrokenCallback2())

    # GitHub #4736
    enumerator = createV1Enumerator()
    enumerator.SetCallback(MyTautomerEnumeratorCallback(self, 50.0))
    enumerator_copy = rdMolStandardize.TautomerEnumerator(enumerator)
    res68 = enumerator.Enumerate(m68)
    res68_copy = enumerator_copy.Enumerate(m68)
    self.assertTrue(res68.status == res68_copy.status)

  def test17PickCanonicalCIPChangeOnChiralCenter(self):

    def get_canonical_taut(res):
      best_idx = max([(rdMolStandardize.TautomerEnumerator.ScoreTautomer(t), i)
                      for i, t in enumerate(res.tautomers)])[1]
      return res.tautomers[best_idx]

    smi = "CC\\C=C(/O)[C@@H](C)C(C)=O"
    mol = Chem.MolFromSmiles(smi)
    rdCIPLabeler.AssignCIPLabels(mol)
    self.assertIsNotNone(mol)
    self.assertEqual(mol.GetAtomWithIdx(5).GetChiralTag(), Chem.ChiralType.CHI_TETRAHEDRAL_CW)
    self.assertEqual(mol.GetAtomWithIdx(5).GetProp("_CIPCode"), "R")

    # here the chirality disappears as the chiral center is itself involved in tautomerism
    te = rdMolStandardize.TautomerEnumerator()
    can_taut = te.Canonicalize(mol)
    self.assertIsNotNone(can_taut)
    self.assertEqual(can_taut.GetAtomWithIdx(5).GetChiralTag(), Chem.ChiralType.CHI_UNSPECIFIED)
    self.assertFalse(can_taut.GetAtomWithIdx(5).HasProp("_CIPCode"))
    self.assertEqual(Chem.MolToSmiles(can_taut), "CCCC(=O)C(C)C(C)=O")

    # here the chirality stays even if the chiral center is itself involved in tautomerism
    # because of the tautomerRemoveSp3Stereo parameter being set to false
    params = rdMolStandardize.CleanupParameters()
    params.tautomerRemoveSp3Stereo = False
    te = rdMolStandardize.TautomerEnumerator(params)
    can_taut = te.Canonicalize(mol)
    self.assertIsNotNone(can_taut)
    rdCIPLabeler.AssignCIPLabels(can_taut)
    self.assertEqual(can_taut.GetAtomWithIdx(5).GetChiralTag(), Chem.ChiralType.CHI_TETRAHEDRAL_CW)
    self.assertEqual(can_taut.GetAtomWithIdx(5).GetProp("_CIPCode"), "S")
    self.assertEqual(Chem.MolToSmiles(can_taut), "CCCC(=O)[C@@H](C)C(C)=O")

    # here the chirality disappears as the chiral center is itself involved in tautomerism
    # the reassignStereo setting has no influence
    te = rdMolStandardize.TautomerEnumerator()
    res = te.Enumerate(mol)
    self.assertEqual(res.status, rdMolStandardize.TautomerEnumeratorStatus.Completed)
    self.assertEqual(len(res.tautomers), 8)
    best_taut = get_canonical_taut(res)
    self.assertIsNotNone(best_taut)
    self.assertEqual(best_taut.GetAtomWithIdx(5).GetChiralTag(), Chem.ChiralType.CHI_UNSPECIFIED)
    self.assertFalse(best_taut.GetAtomWithIdx(5).HasProp("_CIPCode"))
    self.assertEqual(Chem.MolToSmiles(best_taut), "CCCC(=O)C(C)C(C)=O")

    # here the chirality disappears as the chiral center is itself involved in tautomerism
    # the reassignStereo setting has no influence
    params = rdMolStandardize.CleanupParameters()
    params.tautomerReassignStereo = False
    te = rdMolStandardize.TautomerEnumerator(params)
    res = te.Enumerate(mol)
    self.assertEqual(res.status, rdMolStandardize.TautomerEnumeratorStatus.Completed)
    self.assertEqual(len(res.tautomers), 8)
    best_taut = get_canonical_taut(res)
    self.assertIsNotNone(best_taut)
    self.assertEqual(best_taut.GetAtomWithIdx(5).GetChiralTag(), Chem.ChiralType.CHI_UNSPECIFIED)
    self.assertFalse(best_taut.GetAtomWithIdx(5).HasProp("_CIPCode"))
    self.assertEqual(Chem.MolToSmiles(best_taut), "CCCC(=O)C(C)C(C)=O")

    # here the chirality stays even if the chiral center is itself involved in tautomerism
    # because of the tautomerRemoveSp3Stereo parameter being set to false
    # as reassignStereo by default is true, the CIP code has  been recomputed
    # and therefore it is now S (correct)
    params = rdMolStandardize.CleanupParameters()
    params.tautomerRemoveSp3Stereo = False
    te = rdMolStandardize.TautomerEnumerator(params)
    res = te.Enumerate(mol)
    self.assertEqual(res.status, rdMolStandardize.TautomerEnumeratorStatus.Completed)
    self.assertEqual(len(res.tautomers), 8)
    best_taut = get_canonical_taut(res)
    rdCIPLabeler.AssignCIPLabels(best_taut)
    self.assertIsNotNone(best_taut)
    self.assertEqual(best_taut.GetAtomWithIdx(5).GetChiralTag(), Chem.ChiralType.CHI_TETRAHEDRAL_CW)
    self.assertEqual(best_taut.GetAtomWithIdx(5).GetProp("_CIPCode"), "S")
    self.assertEqual(Chem.MolToSmiles(best_taut), "CCCC(=O)[C@@H](C)C(C)=O")

    # here the chirality stays even if the chiral center is itself involved in tautomerism
    # because of the tautomerRemoveSp3Stereo parameter being set to false
    # as reassignStereo is false, the CIP code has not been recomputed
    # and therefore it is still R (incorrect)
    params = rdMolStandardize.CleanupParameters()
    params.tautomerRemoveSp3Stereo = False
    params.tautomerReassignStereo = False
    te = rdMolStandardize.TautomerEnumerator(params)
    res = te.Enumerate(mol)
    self.assertEqual(res.status, rdMolStandardize.TautomerEnumeratorStatus.Completed)
    self.assertEqual(len(res.tautomers), 8)
    best_taut = get_canonical_taut(res)
    self.assertIsNotNone(best_taut)
    self.assertEqual(best_taut.GetAtomWithIdx(5).GetChiralTag(), Chem.ChiralType.CHI_TETRAHEDRAL_CW)
    self.assertEqual(best_taut.GetAtomWithIdx(5).GetProp("_CIPCode"), "R")
    self.assertEqual(Chem.MolToSmiles(best_taut), "CCCC(=O)[C@@H](C)C(C)=O")

    smi = "CC\\C=C(/O)[C@@](CC)(C)C(C)=O"
    mol = Chem.MolFromSmiles(smi)
    self.assertIsNotNone(mol)
    rdCIPLabeler.AssignCIPLabels(mol)
    self.assertEqual(mol.GetAtomWithIdx(5).GetProp("_CIPCode"), "S")
    self.assertEqual(mol.GetAtomWithIdx(5).GetChiralTag(), Chem.ChiralType.CHI_TETRAHEDRAL_CW)

    # here the chirality stays no matter how tautomerRemoveSp3Stereo
    # is set as the chiral center is not involved in tautomerism
    te = rdMolStandardize.TautomerEnumerator()
    can_taut = te.Canonicalize(mol)
    self.assertIsNotNone(can_taut)
    rdCIPLabeler.AssignCIPLabels(can_taut)
    self.assertEqual(can_taut.GetAtomWithIdx(5).GetChiralTag(), Chem.ChiralType.CHI_TETRAHEDRAL_CW)
    self.assertEqual(can_taut.GetAtomWithIdx(5).GetProp("_CIPCode"), "R")
    self.assertEqual(Chem.MolToSmiles(can_taut), "CCCC(=O)[C@](C)(CC)C(C)=O")

    params = rdMolStandardize.CleanupParameters()
    params.tautomerRemoveSp3Stereo = False
    te = rdMolStandardize.TautomerEnumerator(params)
    can_taut = te.Canonicalize(mol)
    self.assertIsNotNone(can_taut)
    rdCIPLabeler.AssignCIPLabels(can_taut)
    self.assertEqual(can_taut.GetAtomWithIdx(5).GetChiralTag(), Chem.ChiralType.CHI_TETRAHEDRAL_CW)
    self.assertEqual(can_taut.GetAtomWithIdx(5).GetProp("_CIPCode"), "R")
    self.assertEqual(Chem.MolToSmiles(can_taut), "CCCC(=O)[C@](C)(CC)C(C)=O")

    # as reassignStereo by default is true, the CIP code has been recomputed
    # and therefore it is now R (correct)
    te = rdMolStandardize.TautomerEnumerator()
    res = te.Enumerate(mol)
    self.assertEqual(res.status, rdMolStandardize.TautomerEnumeratorStatus.Completed)
    self.assertEqual(len(res.tautomers), 4)
    best_taut = get_canonical_taut(res)
    self.assertIsNotNone(best_taut)
    rdCIPLabeler.AssignCIPLabels(best_taut)
    self.assertEqual(best_taut.GetAtomWithIdx(5).GetChiralTag(), Chem.ChiralType.CHI_TETRAHEDRAL_CW)
    self.assertEqual(best_taut.GetAtomWithIdx(5).GetProp("_CIPCode"), "R")
    self.assertEqual(Chem.MolToSmiles(best_taut), "CCCC(=O)[C@](C)(CC)C(C)=O")

    # as reassignStereo is false, the CIP code has not been recomputed
    # and therefore it is still S (incorrect)
    params = rdMolStandardize.CleanupParameters()
    params.tautomerReassignStereo = False
    te = rdMolStandardize.TautomerEnumerator(params)
    res = te.Enumerate(mol)
    self.assertEqual(res.status, rdMolStandardize.TautomerEnumeratorStatus.Completed)
    self.assertEqual(len(res.tautomers), 4)
    best_taut = get_canonical_taut(res)
    self.assertIsNotNone(best_taut)
    self.assertEqual(best_taut.GetAtomWithIdx(5).GetChiralTag(), Chem.ChiralType.CHI_TETRAHEDRAL_CW)
    self.assertEqual(best_taut.GetAtomWithIdx(5).GetProp("_CIPCode"), "S")
    self.assertEqual(Chem.MolToSmiles(best_taut), "CCCC(=O)[C@](C)(CC)C(C)=O")

    # as reassignStereo by default is true, the CIP code has  been recomputed
    # and therefore it is now R (correct)
    params = rdMolStandardize.CleanupParameters()
    params.tautomerRemoveSp3Stereo = False
    te = rdMolStandardize.TautomerEnumerator(params)
    res = te.Enumerate(mol)
    self.assertEqual(res.status, rdMolStandardize.TautomerEnumeratorStatus.Completed)
    self.assertEqual(len(res.tautomers), 4)
    best_taut = get_canonical_taut(res)
    rdCIPLabeler.AssignCIPLabels(best_taut)
    self.assertIsNotNone(best_taut)
    self.assertEqual(best_taut.GetAtomWithIdx(5).GetChiralTag(), Chem.ChiralType.CHI_TETRAHEDRAL_CW)
    self.assertEqual(best_taut.GetAtomWithIdx(5).GetProp("_CIPCode"), "R")
    self.assertEqual(Chem.MolToSmiles(best_taut), "CCCC(=O)[C@](C)(CC)C(C)=O")

    # here the chirality stays even if the tautomerRemoveSp3Stereo parameter
    # is set to false as the chiral center is not involved in tautomerism
    # as reassignStereo is false, the CIP code has not been recomputed
    # and therefore it is still S (incorrect)
    params = rdMolStandardize.CleanupParameters()
    params.tautomerRemoveSp3Stereo = False
    params.tautomerReassignStereo = False
    te = rdMolStandardize.TautomerEnumerator(params)
    res = te.Enumerate(mol)
    self.assertEqual(res.status, rdMolStandardize.TautomerEnumeratorStatus.Completed)
    self.assertEqual(len(res.tautomers), 4)
    best_taut = get_canonical_taut(res)
    self.assertIsNotNone(best_taut)
    self.assertEqual(best_taut.GetAtomWithIdx(5).GetChiralTag(), Chem.ChiralType.CHI_TETRAHEDRAL_CW)
    self.assertEqual(best_taut.GetAtomWithIdx(5).GetProp("_CIPCode"), "S")
    self.assertEqual(Chem.MolToSmiles(best_taut), "CCCC(=O)[C@](C)(CC)C(C)=O")

  def test18TautomerEnumeratorResultIter(self):
    smi = "Cc1nnc(NC(=O)N2CCN(Cc3ccc(F)cc3)C(=O)C2)s1"
    mol = Chem.MolFromSmiles(smi)
    self.assertIsNotNone(mol)
    te = rdMolStandardize.TautomerEnumerator()
    res = te.Enumerate(mol)
    res_it = iter(res)
    i = 0
    while 1:
      try:
        t = next(res_it)
      except StopIteration:
        break
      self.assertEqual(Chem.MolToSmiles(t), Chem.MolToSmiles(res[i]))
      i += 1
    self.assertEqual(i, len(res))
    res_it = iter(res)
    i = -len(res)
    while 1:
      try:
        t = next(res_it)
      except StopIteration:
        break
      self.assertEqual(Chem.MolToSmiles(t), Chem.MolToSmiles(res[i]))
      i += 1
    self.assertEqual(i, 0)

  def test19NormalizeFromParams(self):
    params = rdMolStandardize.CleanupParameters()
    params.normalizationsFile = "ThisFileDoesNotExist.txt"
    with self.assertRaises(OSError):
      rdMolStandardize.NormalizerFromParams(params)

  def test20NoneHandling(self):
    with self.assertRaises(ValueError):
      rdMolStandardize.ChargeParent(None)
    with self.assertRaises(ValueError):
      rdMolStandardize.Cleanup(None)
    with self.assertRaises(ValueError):
      rdMolStandardize.FragmentParent(None)
    with self.assertRaises(ValueError):
      rdMolStandardize.Normalize(None)
    with self.assertRaises(ValueError):
      rdMolStandardize.Reionize(None)

  def test21UpdateFromJSON(self):
    params = rdMolStandardize.CleanupParameters()
    # note: these actual parameters aren't useful... they are for testing
    rdMolStandardize.UpdateParamsFromJSON(
      params, """{
    "normalizationData":[
      {"name":"silly 1","smarts":"[Cl:1]>>[F:1]"},
      {"name":"silly 2","smarts":"[Br:1]>>[F:1]"}
    ],
    "acidbaseData":[
      {"name":"-CO2H","acid":"C(=O)[OH]","base":"C(=O)[O-]"},
      {"name":"phenol","acid":"c[OH]","base":"c[O-]"}
    ],
    "fragmentData":[
      {"name":"hydrogen", "smarts":"[H]"}, 
      {"name":"fluorine", "smarts":"[F]"}, 
      {"name":"chlorine", "smarts":"[Cl]"}
    ],
    "tautomerTransformData":[
      {"name":"1,3 (thio)keto/enol f","smarts":"[CX4!H0]-[C]=[O,S,Se,Te;X1]","bonds":"","charges":""},
      {"name":"1,3 (thio)keto/enol r","smarts":"[O,S,Se,Te;X2!H0]-[C]=[C]"}
    ]}""")

    m = Chem.MolFromSmiles("CCC=O")
    te = rdMolStandardize.TautomerEnumerator(params)
    tauts = [Chem.MolToSmiles(x) for x in te.Enumerate(m)]
    self.assertEqual(tauts, ["CC=CO", "CCC=O"])
    self.assertEqual(Chem.MolToSmiles(rdMolStandardize.CanonicalTautomer(m, params)), "CCC=O")
    # now with defaults
    te = rdMolStandardize.TautomerEnumerator()
    tauts = [Chem.MolToSmiles(x) for x in te.Enumerate(m)]
    self.assertEqual(tauts, ["CC=CO", "CCC=O"])
    self.assertEqual(Chem.MolToSmiles(rdMolStandardize.CanonicalTautomer(m)), "CCC=O")

    m = Chem.MolFromSmiles('ClCCCBr')
    nm = rdMolStandardize.Normalize(m, params)
    self.assertEqual(Chem.MolToSmiles(nm), "FCCCF")
    # now with defaults
    nm = rdMolStandardize.Normalize(m)
    self.assertEqual(Chem.MolToSmiles(nm), "ClCCCBr")

    m = Chem.MolFromSmiles('c1cc([O-])cc(C(=O)O)c1')
    nm = rdMolStandardize.Reionize(m, params)
    self.assertEqual(Chem.MolToSmiles(nm), "O=C([O-])c1cccc(O)c1")
    # now with defaults
    nm = rdMolStandardize.Reionize(m)
    self.assertEqual(Chem.MolToSmiles(nm), "O=C([O-])c1cccc(O)c1")

    m = Chem.MolFromSmiles('C1=C(C=CC(=C1)[S]([O-])=O)[S](O)(=O)=O')
    nm = rdMolStandardize.Reionize(m, params)
    self.assertEqual(Chem.MolToSmiles(nm), "O=S([O-])c1ccc(S(=O)(=O)O)cc1")
    # now with defaults
    nm = rdMolStandardize.Reionize(m)
    self.assertEqual(Chem.MolToSmiles(nm), "O=S(O)c1ccc(S(=O)(=O)[O-])cc1")

    m = Chem.MolFromSmiles('[F-].[Cl-].[Br-].CC')
    nm = rdMolStandardize.RemoveFragments(m, params)
    self.assertEqual(Chem.MolToSmiles(nm), "CC.[Br-]")
    # now with defaults
    nm = rdMolStandardize.RemoveFragments(m)
    self.assertEqual(Chem.MolToSmiles(nm), "CC")

  def test22StandardizeInPlace(self):
    m = Chem.MolFromSmiles("O=N(=O)-C(O[Fe])C(C(=O)O)C-N(=O)=O")
    rdMolStandardize.CleanupInPlace(m)
    self.assertEqual(Chem.MolToSmiles(m), "O=C([O-])C(C[N+](=O)[O-])C(O)[N+](=O)[O-].[Fe+]")

    m = Chem.MolFromSmiles('[F-].[Cl-].[Br-].CC')
    rdMolStandardize.RemoveFragmentsInPlace(m)
    self.assertEqual(Chem.MolToSmiles(m), "CC")

    m = Chem.MolFromSmiles('C1=C(C=CC(=C1)[S]([O-])=O)[S](O)(=O)=O')
    rdMolStandardize.ReionizeInPlace(m)
    self.assertEqual(Chem.MolToSmiles(m), "O=S(O)c1ccc(S(=O)(=O)[O-])cc1")

    m = Chem.MolFromSmiles('CCO[Fe]')
    rdMolStandardize.DisconnectOrganometallicsInPlace(m)
    self.assertEqual(Chem.MolToSmiles(m), "CCO.[Fe]")

    m = Chem.MolFromSmiles(r"C[N+](C)=C\C=C\[O-]")
    rdMolStandardize.NormalizeInPlace(m)
    self.assertEqual(Chem.MolToSmiles(m), "CN(C)C=CC=O")

  def test23CleanupInPlaceMT(self):
    ind = (("O=N(=O)-C(O[Fe])C(C(=O)O)C-N(=O)=O",
            "O=C([O-])C(C[N+](=O)[O-])C(O)[N+](=O)[O-].[Fe+]"),
           ("O=N(=O)-CC(O[Fe])C(C(=O)O)C-N(=O)=O",
            "O=C([O-])C(C[N+](=O)[O-])C(O)C[N+](=O)[O-].[Fe+]"),
           ("O=N(=O)-CCC(O[Fe])C(C(=O)O)C-N(=O)=O",
            "O=C([O-])C(C[N+](=O)[O-])C(O)CC[N+](=O)[O-].[Fe+]"))
    for i in range(4):
      ind = ind + ind
    ms = [Chem.MolFromSmiles(x) for x, y in ind]
    rdMolStandardize.CleanupInPlace(ms, 4)
    self.assertEqual([Chem.MolToSmiles(m) for m in ms], [y for x, y in ind])

  def test24NormalizeInPlaceMT(self):
    ind = (("O=N(=O)-CC-N(=O)=O", "O=[N+]([O-])CC[N+](=O)[O-]"),
           ("O=N(=O)-CCC-N(=O)=O", "O=[N+]([O-])CCC[N+](=O)[O-]"), ("O=N(=O)-CCCC-N(=O)=O",
                                                                    "O=[N+]([O-])CCCC[N+](=O)[O-]"))
    for i in range(4):
      ind = ind + ind
    ms = [Chem.MolFromSmiles(x) for x, y in ind]
    rdMolStandardize.NormalizeInPlace(ms, 4)
    self.assertEqual([Chem.MolToSmiles(m) for m in ms], [y for x, y in ind])

  def test25ReionizeInPlaceMT(self):
    ind = (("c1cc([O-])cc(C(=O)O)c1", "O=C([O-])c1cccc(O)c1"),
           ("c1cc(C[O-])cc(C(=O)O)c1", "O=C([O-])c1cccc(CO)c1"), ("c1cc(CC[O-])cc(C(=O)O)c1",
                                                                  "O=C([O-])c1cccc(CCO)c1"))
    for i in range(4):
      ind = ind + ind
    ms = [Chem.MolFromSmiles(x) for x, y in ind]
    rdMolStandardize.ReionizeInPlace(ms, 4)
    self.assertEqual([Chem.MolToSmiles(m) for m in ms], [y for x, y in ind])

  def test26RemoveFragmentsInPlaceMT(self):
    ind = (("CCCC.Cl.[Na]", "CCCC"), ("CCCCO.Cl.[Na]", "CCCCO"), ("CCOC.Cl.[Na]", "CCOC"))
    for i in range(4):
      ind = ind + ind
    ms = [Chem.MolFromSmiles(x) for x, y in ind]
    rdMolStandardize.RemoveFragmentsInPlace(ms, 4)
    self.assertEqual([Chem.MolToSmiles(m) for m in ms], [y for x, y in ind])

  def test27ChargeParentInPlaceMT(self):
    ind = (("O=C([O-])c1ccccc1", "O=C(O)c1ccccc1"), ("CCCCO.Cl.[Na]", "CCCCO"),
           ("[N+](=O)([O-])[O-].[CH2]", "[CH2]"))
    lfParams = rdMolStandardize.CleanupParameters()
    lfParams.preferOrganic = True
    for x, y in ind:
      m2 = Chem.MolFromSmiles(x)
      rdMolStandardize.ChargeParentInPlace(m2, lfParams)
      self.assertEqual(Chem.MolToSmiles(m2), y)

    ms = [Chem.MolFromSmiles(x) for x, y in ind]
    for i in range(4):
      ind = ind + ind
    ms = [Chem.MolFromSmiles(x) for x, y in ind]
    rdMolStandardize.ChargeParentInPlace(ms, 4, lfParams)
    self.assertEqual([Chem.MolToSmiles(m) for m in ms], [y for x, y in ind])

  def test28TautomerParentInPlaceMT(self):
    ind = (("[O-]c1ccc(C(=O)O)cc1CC=CO", "O=CCCc1cc(C(=O)[O-])ccc1O"),
           ("[O-]c1ccc(C(=O)O)cc1CC=CO.[Na+]", "O=CCCc1cc(C(=O)[O-])ccc1O.[Na+]"),
           ("[O-]c1ccc(C(=O)O)cc1C[13CH]=CO", "O=C[13CH2]Cc1cc(C(=O)[O-])ccc1O"))
    for x, y in ind:
      m2 = Chem.MolFromSmiles(x)
      rdMolStandardize.TautomerParentInPlace(m2)
      self.assertEqual(Chem.MolToSmiles(m2), y)

    ms = [Chem.MolFromSmiles(x) for x, y in ind]
    for i in range(4):
      ind = ind + ind
    ms = [Chem.MolFromSmiles(x) for x, y in ind]
    rdMolStandardize.TautomerParentInPlace(ms, 4)
    self.assertEqual([Chem.MolToSmiles(m) for m in ms], [y for x, y in ind])

  def test29StereoParentInPlaceMT(self):
    ind = (("F[C@H](O)Cl", "OC(F)Cl"), ("F[C@H](CCO)Cl", "OCCC(F)Cl"), ("F[C@H](CCO)Cl.F[C@H](O)Cl",
                                                                        "OC(F)Cl.OCCC(F)Cl"))
    for x, y in ind:
      m2 = Chem.MolFromSmiles(x)
      rdMolStandardize.StereoParentInPlace(m2)
      self.assertEqual(Chem.MolToSmiles(m2), y)

    ms = [Chem.MolFromSmiles(x) for x, y in ind]
    for i in range(4):
      ind = ind + ind
    ms = [Chem.MolFromSmiles(x) for x, y in ind]
    rdMolStandardize.StereoParentInPlace(ms, 4)
    self.assertEqual([Chem.MolToSmiles(m) for m in ms], [y for x, y in ind])

  def test30FragmentParentInPlaceMT(self):
    ind = (("O=C([O-])c1ccccc1", "O=C([O-])c1ccccc1"), ("CCCCO.Cl.[Na]", "CCCC[O-]"),
           ("[N+](=O)([O-])[O-].[CH2]", "[CH2]"))
    lfParams = rdMolStandardize.CleanupParameters()
    lfParams.preferOrganic = True
    for x, y in ind:
      m2 = Chem.MolFromSmiles(x)
      rdMolStandardize.FragmentParentInPlace(m2, lfParams)
      self.assertEqual(Chem.MolToSmiles(m2), y)

    ms = [Chem.MolFromSmiles(x) for x, y in ind]
    for i in range(4):
      ind = ind + ind
    ms = [Chem.MolFromSmiles(x) for x, y in ind]
    rdMolStandardize.FragmentParentInPlace(ms, 4, lfParams)
    self.assertEqual([Chem.MolToSmiles(m) for m in ms], [y for x, y in ind])

  def test31IsotopeParentInPlaceMT(self):
    ind = (("[13CH3]C", "CC"), ("[13CH3]C.C", "C.CC"), ("[13CH3][12CH3]", "CC"))
    for x, y in ind:
      m2 = Chem.MolFromSmiles(x)
      rdMolStandardize.IsotopeParentInPlace(m2)
      self.assertEqual(Chem.MolToSmiles(m2), y)

    ms = [Chem.MolFromSmiles(x) for x, y in ind]
    for i in range(4):
      ind = ind + ind
    ms = [Chem.MolFromSmiles(x) for x, y in ind]
    rdMolStandardize.IsotopeParentInPlace(ms, 4)
    self.assertEqual([Chem.MolToSmiles(m) for m in ms], [y for x, y in ind])

  def test32SuperParentInPlaceMT(self):
    ind = (("[O-]c1ccc(C(=O)O)cc1CC=CO", "O=CCCc1cc(C(=O)O)ccc1O"),
           ("[O-]c1ccc(C(=O)O)cc1CC=CO.[Na+]",
            "O=CCCc1cc(C(=O)O)ccc1O"), ("[O-]c1ccc(C(=O)O)cc1C[13CH]=CO", "O=CCCc1cc(C(=O)O)ccc1O"))
    for x, y in ind:
      m2 = Chem.MolFromSmiles(x)
      rdMolStandardize.SuperParentInPlace(m2)
      self.assertEqual(Chem.MolToSmiles(m2), y)

    ms = [Chem.MolFromSmiles(x) for x, y in ind]
    for i in range(4):
      ind = ind + ind
    ms = [Chem.MolFromSmiles(x) for x, y in ind]
    rdMolStandardize.SuperParentInPlace(ms, 4)
    self.assertEqual([Chem.MolToSmiles(m) for m in ms], [y for x, y in ind])

  def test33MolBlockValidation(self):
    # featuresValidation
    mol = Chem.MolFromMolBlock(
      '''
  Mrv2311 01162413552D          

  0  0  0     0  0            999 V3000
M  V30 BEGIN CTAB
M  V30 COUNTS 2 1 0 0 0
M  V30 BEGIN ATOM
M  V30 1 R# -17.3747 6.9367 0 0 RGROUPS=(1 0)
M  V30 2 C -18.7083 6.1667 0 0
M  V30 END ATOM
M  V30 BEGIN BOND
M  V30 1 1 2 1
M  V30 END BOND
M  V30 END CTAB
M  END
''', sanitize=False)

    validator = rdMolStandardize.FeaturesValidation()
    errinfo = validator.validate(mol)
    self.assertEqual(len(errinfo), 1)
    self.assertEqual(errinfo[0], "ERROR: [FeaturesValidation] Query atom 0 is not allowed")
    validator.allowDummies = True
    validator.allowQueries = True
    errinfo = validator.validate(mol)
    self.assertEqual(len(errinfo), 0)

    mol = Chem.MolFromMolBlock('''
  Mrv2311 01162411552D          

  0  0  0     0  0            999 V3000
M  V30 BEGIN CTAB
M  V30 COUNTS 4 3 0 0 0
M  V30 BEGIN ATOM
M  V30 1 C -18.208 8.52 0 0 CFG=2
M  V30 2 F -19.5417 7.75 0 0
M  V30 3 C -16.8743 7.75 0 0
M  V30 4 Cl -18.208 10.06 0 0
M  V30 END ATOM
M  V30 BEGIN BOND
M  V30 1 1 1 3 CFG=1
M  V30 2 1 2 1
M  V30 3 1 1 4
M  V30 END BOND
M  V30 BEGIN COLLECTION
M  V30 MDLV30/STERAC1 ATOMS=(1 1)
M  V30 END COLLECTION
M  V30 END CTAB
M  END
''')

    # enhanced stereo features are by default disallowed
    validator = rdMolStandardize.FeaturesValidation()
    errinfo = validator.validate(mol, True)
    self.assertEqual(len(errinfo), 1)
    self.assertEqual(
      errinfo[0], "ERROR: [FeaturesValidation] Enhanced stereochemistry features are not allowed")

    # allow enhanced stereo
    validator = rdMolStandardize.FeaturesValidation(True)
    errinfo = validator.validate(mol, True)
    self.assertEqual(len(errinfo), 0)
    validator.allowEnhancedStereo = True
    errinfo = validator.validate(mol)
    self.assertEqual(len(errinfo), 0)

    mol = Chem.MolFromMolBlock(
      '''
  Mrv2311 02272411562D          

  0  0  0     0  0            999 V3000
M  V30 BEGIN CTAB
M  V30 COUNTS 7 7 0 0 0
M  V30 BEGIN ATOM
M  V30 1 C -10.3542 4.29 0 0
M  V30 2 C -11.6879 3.52 0 0
M  V30 3 C -11.6879 1.9798 0 0
M  V30 4 N -10.3542 1.21 0 0
M  V30 5 C -9.0204 1.9798 0 0
M  V30 6 C -9.0204 3.52 0 0
M  V30 7 C -10.3542 5.83 0 0
M  V30 END ATOM
M  V30 BEGIN BOND
M  V30 1 4 1 2
M  V30 2 4 1 6
M  V30 3 4 2 3
M  V30 4 4 5 6
M  V30 5 1 1 7
M  V30 6 4 3 4
M  V30 7 4 4 5
M  V30 END BOND
M  V30 END CTAB
M  END
''', sanitize=False)

    # aromatic bonds are by default disallowed
    validator = rdMolStandardize.FeaturesValidation()
    errinfo = validator.validate(mol, True)
    self.assertEqual(len(errinfo), 6)
    self.assertEqual(errinfo[0],
                     "ERROR: [FeaturesValidation] Bond 0 of aromatic type is not allowed")
    validator.allowAromaticBondType = True
    errinfo = validator.validate(mol)
    self.assertEqual(len(errinfo), 0)

    # allow aromatic bonds
    validator = rdMolStandardize.FeaturesValidation(False, True)
    errinfo = validator.validate(mol, True)
    self.assertEqual(len(errinfo), 0)

    # disallowedRadicalValidation
    mol = Chem.MolFromMolBlock(
      '''
  Mrv2311 02082417212D          

  0  0  0     0  0            999 V3000
M  V30 BEGIN CTAB
M  V30 COUNTS 2 1 0 0 0
M  V30 BEGIN ATOM
M  V30 1 C -20.9372 7.145 0 0 RAD=2
M  V30 2 C -22.2708 6.375 0 0
M  V30 END ATOM
M  V30 BEGIN BOND
M  V30 1 1 2 1
M  V30 END BOND
M  V30 END CTAB
M  END
''', sanitize=False)

    validator = rdMolStandardize.DisallowedRadicalValidation()
    errinfo = validator.validate(mol)
    self.assertEqual(len(errinfo), 1)
    self.assertEqual(errinfo[0],
                     "ERROR: [DisallowedRadicalValidation] The radical at atom 0 is not allowed")

    # is2DValidation
    mol = Chem.MolFromMolBlock(
      '''
                    2D          

  0  0  0     0  0            999 V3000
M  V30 BEGIN CTAB
M  V30 COUNTS 2 1 0 0 0
M  V30 BEGIN ATOM
M  V30 1 C 0.8753 4.9367 0 0
M  V30 2 C -0.4583 4.1667 0 0
M  V30 END ATOM
M  V30 BEGIN BOND
M  V30 1 1 2 1
M  V30 END BOND
M  V30 END CTAB
M  END
''', sanitize=False)

    validator = rdMolStandardize.Is2DValidation()
    errinfo = validator.validate(mol)
    self.assertEqual(len(errinfo), 0)

    conf = mol.GetConformer()
    pos = conf.GetAtomPosition(1)
    self.assertEqual(pos.z, 0.0)
    pos.z = 0.1
    conf.SetAtomPosition(1, pos)

    validator = rdMolStandardize.Is2DValidation()
    errinfo = validator.validate(mol)
    self.assertEqual(len(errinfo), 1)
    self.assertEqual(errinfo[0],
                     "ERROR: [Is2DValidation] The molecule includes non-null Z coordinates")

    validator = rdMolStandardize.Is2DValidation(0.2)
    errinfo = validator.validate(mol)
    self.assertEqual(len(errinfo), 0)

    mol = Chem.MolFromMolBlock(
      '''
                    2D          

  0  0  0     0  0            999 V3000
M  V30 BEGIN CTAB
M  V30 COUNTS 2 1 0 0 0
M  V30 BEGIN ATOM
M  V30 1 C 0.8753 4.9367 0 0
M  V30 2 C -0.4583 4.1667 0.2 0
M  V30 END ATOM
M  V30 BEGIN BOND
M  V30 1 1 2 1
M  V30 END BOND
M  V30 END CTAB
M  END
''', sanitize=False)
    validator = rdMolStandardize.Is2DValidation()
    errinfo = validator.validate(mol)
    self.assertEqual(len(errinfo), 1)
    self.assertEqual(errinfo[0],
                     "ERROR: [Is2DValidation] The molecule includes non-null Z coordinates")

    # AtomClashValidation
    mol = Chem.MolFromMolBlock(
      '''
                    2D          

  0  0  0     0  0            999 V3000
M  V30 BEGIN CTAB
M  V30 COUNTS 6 5 0 0 0
M  V30 BEGIN ATOM
M  V30 1 C -1.6667 6.2067 0 0
M  V30 2 C -3.0004 5.4367 0 0
M  V30 3 C -3.0004 3.8965 0 0
M  V30 4 C -1.6667 3.1267 0 0
M  V30 5 C -0.3329 4.6000 0 0
M  V30 6 C -0.3329 4.7000 0 0
M  V30 END ATOM
M  V30 BEGIN BOND
M  V30 1 1 1 2
M  V30 2 1 1 6
M  V30 3 1 2 3
M  V30 4 1 3 4
M  V30 5 1 4 5
M  V30 END BOND
M  V30 END CTAB
M  END
''', sanitize=False)

    validator = rdMolStandardize.Layout2DValidation()
    errinfo = validator.validate(mol)
    self.assertEqual(len(errinfo), 1)
    self.assertEqual(errinfo[0], "ERROR: [Layout2DValidation] Atom 4 is too close to atom 5")

    validator = rdMolStandardize.Layout2DValidation(1e-3)
    errinfo = validator.validate(mol)
    self.assertEqual(len(errinfo), 0)

    mol = Chem.MolFromMolBlock(
      '''
          10052311582D          

  0  0  0     0  0            999 V3000
M  V30 BEGIN CTAB
M  V30 COUNTS 5 4 0 0 0
M  V30 BEGIN ATOM
M  V30 1 Br 0.0003 7.27 0 0
M  V30 2 C -1.3333 6.5 0 0
M  V30 3 F -2.667 7.27 0 0
M  V30 4 O -1.3333 4.96 0 0
M  V30 5 C 0.0003 5.73 0 0
M  V30 END ATOM
M  V30 BEGIN BOND
M  V30 1 1 2 5 CFG=1
M  V30 2 1 2 3 CFG=3
M  V30 3 1 2 1
M  V30 4 1 2 4
M  V30 END BOND
M  V30 END CTAB
M  END
''', sanitize=False)

    Chem.ReapplyMolBlockWedging(mol)

    validator = rdMolStandardize.StereoValidation()
    errinfo = validator.validate(mol)
    self.assertEqual(len(errinfo), 1)
    self.assertEqual(
      errinfo[0],
      "ERROR: [StereoValidation] Atom 1 has opposing stereo bonds with different up/down orientation"
    )

  def test24Pipeline(self):
    pipeline = rdMolStandardize.Pipeline()

    # invalid input molblock
    molblock = '''
             sldfj;ldskfj sldkjfsd;lkf 
M  V30 BEGIN CTAB
'''
    result = pipeline.run(molblock)
    self.assertEqual(result.stage, rdMolStandardize.PipelineStage.PARSING_INPUT)
    self.assertNotEqual(result.status, rdMolStandardize.PipelineStatus.NO_EVENT)
    self.assertTrue(result.status & rdMolStandardize.PipelineStatus.INPUT_ERROR)

    # R group
    molblock = '''
  Mrv2311 01162413552D          

  0  0  0     0  0            999 V3000
M  V30 BEGIN CTAB
M  V30 COUNTS 2 1 0 0 0
M  V30 BEGIN ATOM
M  V30 1 R# -17.3747 6.9367 0 0 RGROUPS=(1 0)
M  V30 2 C -18.7083 6.1667 0 0
M  V30 END ATOM
M  V30 BEGIN BOND
M  V30 1 1 2 1
M  V30 END BOND
M  V30 END CTAB
M  END
'''
    result = pipeline.run(molblock)
    self.assertEqual(result.stage, rdMolStandardize.PipelineStage.COMPLETED)
    self.assertNotEqual(result.status, rdMolStandardize.PipelineStatus.NO_EVENT)
    self.assertTrue(result.status & rdMolStandardize.PipelineStatus.VALIDATION_ERROR)
    self.assertTrue(result.status & rdMolStandardize.PipelineStatus.FEATURES_VALIDATION_ERROR)

    # no atoms
    molblock = '''
          10052313452D          

  0  0  0     0  0            999 V3000
M  V30 BEGIN CTAB
M  V30 COUNTS 0 0 0 0 0
M  V30 END CTAB
M  END
'''
    result = pipeline.run(molblock)
    self.assertEqual(result.stage, rdMolStandardize.PipelineStage.COMPLETED)
    self.assertNotEqual(result.status, rdMolStandardize.PipelineStatus.NO_EVENT)
    self.assertTrue(result.status & rdMolStandardize.PipelineStatus.VALIDATION_ERROR)
    self.assertTrue(result.status & rdMolStandardize.PipelineStatus.BASIC_VALIDATION_ERROR)

    # neutral quaternary N
    molblock = '''
          10242314442D          

  0  0  0     0  0            999 V3000
M  V30 BEGIN CTAB
M  V30 COUNTS 5 4 0 0 0
M  V30 BEGIN ATOM
M  V30 1 C -1.6247 7.5825 0 0
M  V30 2 N -2.9583 6.8125 0 0
M  V30 3 C -4.292 7.5825 0 0
M  V30 4 C -2.9583 5.2725 0 0
M  V30 5 C -1.6247 6.0425 0 0
M  V30 END ATOM
M  V30 BEGIN BOND
M  V30 1 1 2 1
M  V30 2 1 2 3
M  V30 3 1 2 4
M  V30 4 1 2 5
M  V30 END BOND
M  V30 END CTAB
M  END
'''
    result = pipeline.run(molblock)
    self.assertEqual(result.stage, rdMolStandardize.PipelineStage.COMPLETED)
    self.assertNotEqual(result.status, rdMolStandardize.PipelineStatus.NO_EVENT)
    self.assertTrue(result.status & rdMolStandardize.PipelineStatus.VALIDATION_ERROR)
    #self.assertTrue(result.status & rdMolStandardize.PipelineStatus.STANDARDIZATION_ERROR)
    self.assertEqual(
      result.status,
      (
        rdMolStandardize.PipelineStatus.BASIC_VALIDATION_ERROR
        | rdMolStandardize.PipelineStatus.PREPARE_FOR_STANDARDIZATION_ERROR  #|
        #rdMolStandardize.PipelineStatus.NORMALIZER_STANDARDIZATION_ERROR
      ))

    molblock = '''
                    2D          

  0  0  0     0  0            999 V3000
M  V30 BEGIN CTAB
M  V30 COUNTS 2 1 0 0 0
M  V30 BEGIN ATOM
M  V30 1 C 0.8753 4.9367 0 0
M  V30 2 C -0.4583 4.1667 0.2 0
M  V30 END ATOM
M  V30 BEGIN BOND
M  V30 1 1 2 1
M  V30 END BOND
M  V30 END CTAB
M  END
'''

    result = pipeline.run(molblock)
    self.assertEqual(result.stage, rdMolStandardize.PipelineStage.COMPLETED)
    self.assertNotEqual(result.status, rdMolStandardize.PipelineStatus.NO_EVENT)
    self.assertTrue(result.status & rdMolStandardize.PipelineStatus.VALIDATION_ERROR)
    self.assertTrue(result.status & rdMolStandardize.PipelineStatus.IS2D_VALIDATION_ERROR)

    molblock = '''
                    2D          

  0  0  0     0  0            999 V3000
M  V30 BEGIN CTAB
M  V30 COUNTS 4 3 0 0 0
M  V30 BEGIN ATOM
M  V30 1 C -3.05 5.48 0 0
M  V30 2 C -4.4167 4.6875 0 0
M  V30 3 C -4.3289 6.3627 0 0
M  V30 4 C -3.0 5.5 0 0
M  V30 END ATOM
M  V30 BEGIN BOND
M  V30 1 1 2 1
M  V30 2 1 1 3
M  V30 3 1 3 4
M  V30 END BOND
M  V30 END CTAB
M  END
'''

    result = pipeline.run(molblock)
    self.assertEqual(result.stage, rdMolStandardize.PipelineStage.COMPLETED)
    self.assertNotEqual(result.status, rdMolStandardize.PipelineStatus.NO_EVENT)
    self.assertTrue(result.status & rdMolStandardize.PipelineStatus.VALIDATION_ERROR)
    self.assertTrue(result.status & rdMolStandardize.PipelineStatus.LAYOUT2D_VALIDATION_ERROR)

    molblock = '''
                    2D          

  0  0  0     0  0            999 V3000
M  V30 BEGIN CTAB
M  V30 COUNTS 5 4 0 0 0
M  V30 BEGIN ATOM
M  V30 1 C -1.583 5.7075 0 0
M  V30 2 C -2.9167 4.9375 0 0
M  V30 3 C -1.583 7.2475 0 0
M  V30 4 C -0.2493 4.9375 0.5 0
M  V30 5 C -1.583 4.1675 0 0
M  V30 END ATOM
M  V30 BEGIN BOND
M  V30 1 1 1 2 CFG=1
M  V30 2 1 1 3 CFG=1
M  V30 3 1 1 4
M  V30 4 1 1 5
M  V30 END BOND
M  V30 END CTAB
M  END
'''

    result = pipeline.run(molblock)
    self.assertEqual(result.stage, rdMolStandardize.PipelineStage.COMPLETED)
    self.assertNotEqual(result.status, rdMolStandardize.PipelineStatus.NO_EVENT)
    self.assertTrue(result.status & rdMolStandardize.PipelineStatus.VALIDATION_ERROR)
    self.assertEqual(
      result.status, rdMolStandardize.PipelineStatus.IS2D_VALIDATION_ERROR
      | rdMolStandardize.PipelineStatus.STEREO_VALIDATION_ERROR)

    molblock = '''
          10282320572D          

  0  0  0     0  0            999 V3000
M  V30 BEGIN CTAB
M  V30 COUNTS 5 4 0 0 0
M  V30 BEGIN ATOM
M  V30 1 C -1.0413 5.4992 0 0
M  V30 2 C -2.375 4.7292 0 0
M  V30 3 O -1.0413 7.0392 0 0
M  V30 4 O 0.2924 4.7292 0 0
M  V30 5 Na 0.2924 3.1892 0 0
M  V30 END ATOM
M  V30 BEGIN BOND
M  V30 1 1 2 1
M  V30 2 1 1 4
M  V30 3 2 1 3
M  V30 4 1 4 5
M  V30 END BOND
M  V30 END CTAB
M  END
'''

    result = pipeline.run(molblock)
    self.assertEqual(result.stage, rdMolStandardize.PipelineStage.COMPLETED)
    self.assertEqual((result.status & rdMolStandardize.PipelineStatus.PIPELINE_ERROR),
                     rdMolStandardize.PipelineStatus.NO_EVENT)
    self.assertNotEqual((result.status & rdMolStandardize.PipelineStatus.STRUCTURE_MODIFICATION),
                        rdMolStandardize.PipelineStatus.STRUCTURE_MODIFICATION)
    self.assertEqual((result.status & rdMolStandardize.PipelineStatus.STRUCTURE_MODIFICATION),
                     (rdMolStandardize.PipelineStatus.METALS_DISCONNECTED
                      | rdMolStandardize.PipelineStatus.FRAGMENTS_REMOVED
                      | rdMolStandardize.PipelineStatus.PROTONATION_CHANGED))

    parentMol = Chem.MolFromMolBlock(result.parentMolData, sanitize=False)
    parentSmiles = Chem.MolToSmiles(parentMol)
    self.assertEqual(parentSmiles, "CC(=O)O")

    outputMol = Chem.MolFromMolBlock(result.outputMolData, sanitize=False)
    outputSmiles = Chem.MolToSmiles(outputMol)
    self.assertEqual(outputSmiles, "CC(=O)O")

    molblock = '''
          10282320572D          

  0  0  0     0  0            999 V3000
M  V30 BEGIN CTAB
M  V30 COUNTS 4 3 0 0 0
M  V30 BEGIN ATOM
M  V30 1 N -1.0413 5.4992 0 0
M  V30 2 C -2.375 4.7292 0 0
M  V30 3 O -1.0413 7.0392 0 0
M  V30 4 O 0.2924 4.7292 0 0
M  V30 END ATOM
M  V30 BEGIN BOND
M  V30 1 1 2 1
M  V30 2 2 1 4
M  V30 3 2 1 3
M  V30 END BOND
M  V30 END CTAB
M  END
'''

    result = pipeline.run(molblock)
    self.assertEqual(result.stage, rdMolStandardize.PipelineStage.COMPLETED)
    # nitro groups are cleaned-up in a pre-standardization step
    self.assertEqual((result.status & rdMolStandardize.PipelineStatus.PIPELINE_ERROR),
                     rdMolStandardize.PipelineStatus.NO_EVENT)
    self.assertEqual((result.status & rdMolStandardize.PipelineStatus.STRUCTURE_MODIFICATION),
                     rdMolStandardize.PipelineStatus.NO_EVENT)

    parentMol = Chem.MolFromMolBlock(result.parentMolData, sanitize=False)
    parentSmiles = Chem.MolToSmiles(parentMol)
    self.assertEqual(parentSmiles, "C[N+](=O)[O-]")

    outputMol = Chem.MolFromMolBlock(result.outputMolData, sanitize=False)
    outputSmiles = Chem.MolToSmiles(outputMol)
    self.assertEqual(outputSmiles, "C[N+](=O)[O-]")

    molblock = '''
          10282320572D          

  0  0  0     0  0            999 V3000
M  V30 BEGIN CTAB
M  V30 COUNTS 6 5 0 0 0
M  V30 BEGIN ATOM
M  V30 1 C -1.0413 5.4992 0 0
M  V30 2 C -2.375 4.7292 0 0
M  V30 3 O -1.0413 7.0392 0 0
M  V30 4 O 0.2924 4.7292 0 0
M  V30 5 N -3.7087 5.4992 0 0 CHG=1
M  V30 6 Na 0.2924 3.1892 0 0
M  V30 END ATOM
M  V30 BEGIN BOND
M  V30 1 1 2 1
M  V30 2 1 1 4
M  V30 3 2 1 3
M  V30 4 1 2 5
M  V30 5 1 4 6
M  V30 END BOND
M  V30 END CTAB
M  END
'''

    result = pipeline.run(molblock)
    self.assertEqual(result.stage, rdMolStandardize.PipelineStage.COMPLETED)
    self.assertEqual((result.status & rdMolStandardize.PipelineStatus.PIPELINE_ERROR),
                     rdMolStandardize.PipelineStatus.NO_EVENT)
    self.assertNotEqual((result.status & rdMolStandardize.PipelineStatus.STRUCTURE_MODIFICATION),
                        rdMolStandardize.PipelineStatus.STRUCTURE_MODIFICATION)
    self.assertEqual((result.status & rdMolStandardize.PipelineStatus.STRUCTURE_MODIFICATION),
                     (rdMolStandardize.PipelineStatus.METALS_DISCONNECTED
                      | rdMolStandardize.PipelineStatus.FRAGMENTS_REMOVED))

    parentMol = Chem.MolFromMolBlock(result.parentMolData, sanitize=False)
    parentSmiles = Chem.MolToSmiles(parentMol)
    self.assertEqual(parentSmiles, "NCC(=O)O")

    outputMol = Chem.MolFromMolBlock(result.outputMolData, sanitize=False)
    outputSmiles = Chem.MolToSmiles(outputMol)
    self.assertEqual(outputSmiles, "[NH3+]CC(=O)[O-]")

  def test25PipelineNormalizerOptions(self):
    options = rdMolStandardize.PipelineOptions()
    # run the pipeline w/ the RDKit default normalizer transforms
    options.normalizerData = ''
    pipeline = rdMolStandardize.Pipeline(options)

    molblock = '''
  Mrv2311 02072415362D          

  0  0  0     0  0            999 V3000
M  V30 BEGIN CTAB
M  V30 COUNTS 4 3 0 0 0
M  V30 BEGIN ATOM
M  V30 1 S -10.3538 4.27 0 0
M  V30 2 C -11.6875 3.5 0 0
M  V30 3 O -10.3538 5.81 0 0
M  V30 4 C -9.0201 3.5 0 0
M  V30 END ATOM
M  V30 BEGIN BOND
M  V30 1 1 2 1
M  V30 2 1 1 4
M  V30 3 2 1 3
M  V30 END BOND
M  V30 END CTAB
M  END
'''
    result = pipeline.run(molblock)
    self.assertEqual(result.stage, rdMolStandardize.PipelineStage.COMPLETED)
    self.assertEqual((result.status & rdMolStandardize.PipelineStatus.PIPELINE_ERROR),
                     rdMolStandardize.PipelineStatus.NO_EVENT)
    self.assertNotEqual((result.status & rdMolStandardize.PipelineStatus.STRUCTURE_MODIFICATION),
                        rdMolStandardize.PipelineStatus.STRUCTURE_MODIFICATION)
    self.assertEqual((result.status & rdMolStandardize.PipelineStatus.STRUCTURE_MODIFICATION),
                     rdMolStandardize.PipelineStatus.NORMALIZATION_APPLIED)

    outputMol = Chem.MolFromMolBlock(result.outputMolData, sanitize=False)
    outputSmiles = Chem.MolToSmiles(outputMol)
    self.assertEqual(outputSmiles, "C[S+](C)[O-]")

  def test26PipelineAllowEmptyMoleculesOption(self):
    options = rdMolStandardize.PipelineOptions()
    options.allowEmptyMolecules = True
    pipeline = rdMolStandardize.Pipeline(options)

    # no atoms
    molblock = '''
          10052313452D          

  0  0  0     0  0            999 V3000
M  V30 BEGIN CTAB
M  V30 COUNTS 0 0 0 0 0
M  V30 END CTAB
M  END
'''
    result = pipeline.run(molblock)
    self.assertEqual(result.stage, rdMolStandardize.PipelineStage.COMPLETED)
    self.assertEqual(result.status, rdMolStandardize.PipelineStatus.NO_EVENT)

  def testCustomScoreFuncs(self):
    smi = "CC\\C=C(/O)[C@@H](C)C(C)=O"
    m = Chem.MolFromSmiles(smi)
    self.assertEqual(rdMolStandardize.ScoreRings(m), 0)
    self.assertEqual(rdMolStandardize.ScoreHeteroHs(m), 0)
    self.assertEqual(rdMolStandardize.ScoreSubstructs(m), 6)

    # check the default terms
    terms = rdMolStandardize.GetDefaultTautomerScoreSubstructs()
    for term, (name, smarts, score) in zip(terms, [["benzoquinone", "[#6]1([#6]=[#6][#6]([#6]=[#6]1)=,:[N,S,O])=,:[N,S,O]",
                                                    25],
                                                   ["oxim", "[#6]=[N][OH]", 4],
                                                   ["C=O", "[#6]=,:[#8]", 2],
                                                   ["N=O", "[#7]=,:[#8]", 2],
                                                   ["P=O", "[#15]=,:[#8]", 2],
                                                   ["C=hetero", "[C]=[!#1;!#6]", 1],
                                                   ["C(=hetero)-hetero", "[C](=[!#1;!#6])[!#1;!#6]", 2],
                                                   ["aromatic C = exocyclic N", "[c]=!@[N]", -1],
                                                   ["methyl", "[CX4H3]", 1],
                                                   ["guanidine terminal=N", "[#7]C(=[NR0])[#7H0]", 1],
                                                   ["guanidine endocyclic=N", "[#7;R][#6;R]([N])=[#7;R]", 2],
                                                   ["aci-nitro", "[#6]=[N+]([O-])[OH]", -4]]):
      self.assertEqual((term.name, term.smarts, term.score), (name, smarts, score))

      # make sure we can pass in our own terms
      terms = rdMolStandardize.SubstructTermVector()
      terms.append(rdMolStandardize.SubstructTerm("C=0", "[#6]=,:[#8]", 1000))
      self.assertEqual(rdMolStandardize.ScoreSubstructs(m, terms), 1000)

      self.assertEqual(rdMolStandardize.ScoreSubstructs(
        m, rdMolStandardize.GetDefaultTautomerScoreSubstructs()), 6)

      enumerator = rdMolStandardize.TautomerEnumerator()
      m2 = Chem.MolFromSmiles("C1(=CCCCC1)O")
      
      ctaut = enumerator.Canonicalize(m2)
      self.assertEqual(Chem.MolToSmiles(ctaut), "O=C1CCCCC1")

      # duplicate the normal scoring function
      def score_func1(mol):
        return (rdMolStandardize.ScoreRings(mol) + rdMolStandardize.ScoreHeteroHs(mol) +
                rdMolStandardize.ScoreSubstructs(mol))

      ctaut = enumerator.Canonicalize(m2, score_func1)
      self.assertEqual(Chem.MolToSmiles(ctaut), "O=C1CCCCC1")

      # pull a single tautomer out of the mix
      def score_func2(mol):
        if Chem.MolToSmiles(mol) == Chem.CanonSmiles("C1(=CCCCC1)O"):
          return 100_000
        return 0
      
      ctaut = enumerator.Canonicalize(m2, score_func2)
      self.assertEqual(Chem.MolToSmiles(ctaut), Chem.CanonSmiles("C1(=CCCCC1)O"))
      
    
if __name__ == "__main__":
  unittest.main()
